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Cserep G.B.,Hungarian Academy of Sciences | Baranyai Z.,MTA ELTE Research Group of Peptide Chemistry | Komaromy D.,Hungarian Academy of Sciences | Horvati K.,MTA ELTE Research Group of Peptide Chemistry | And 2 more authors.
Tetrahedron | Year: 2014

Fluorescent tagging of Cys-containing peptides is presented herein. The procedure follows a two-step sequential reaction scheme using thiol specific bifunctional chemical reporters and fluorogenic labels. Vinyl-sulfone bearing chemical reporters have been synthesized and demonstrated to selectively modify cysteine under physiological conditions in the presence of other nucleophilic amino acids. Bifunctional chemical reporters decorated with a terminal alkyne moiety, suitable for modification with azide containing fluorogenic labels were also synthesized. Such fluorogenic (turn on) labels in combination with these new vinyl-sulfone tags can be used generally in fluorescent modulation schemes of thiol-bearing biomolecules. © 2014 Elsevier Ltd. All rights reserved.


Schafer B.,Hungarian Academy of Sciences | Orban E.,MTA ELTE Research Group of Peptide Chemistry | Fiser G.,Hungarian Academy of Sciences | Marton A.,Hungarian Academy of Sciences | And 2 more authors.
Tetrahedron Letters | Year: 2016

Cholesteryl lipoprotein semisynthesis was accomplished via a copper-catalyzed azide-alkyne cycloaddition on the surface of live cells. In this convergent synthesis an azido-cholesterol was introduced into the cell membrane without the application of detergents followed by conjugation of the C-terminal alkyne modified protein. This cytocompatible method resulted in a folded membrane-anchored protein containing a small molecule fluorophore in the lipid headgroup. © 2016 Elsevier Ltd. All rights reserved.


Skiba J.,University of Lodz | Karpowicz R.,University of Lodz | Szabo I.,MTA ELTE Research Group of Peptide Chemistry | Therrien B.,University of Neuchatel | Kowalski K.,University of Lodz
Journal of Organometallic Chemistry | Year: 2015

A convenient synthesis of ferrocenyl-4-thiothymine-3,6-dihydro-2H-thiopyrane (3) and ferrocenyl-thymine-3,6-dihydro-2H-thiopyrane (4) by a hetero-Diels-Alder cycloaddition reaction is reported. These complexes represent new class of ferrocenyl nucleobase derivatives. The 2H-thiopyrane ring mimics the sugar subunit present in natural nucleosides and nucleotides. The X-ray crystal structure analysis of the precursor thioketone (1) showed that individual molecules of 1 form H-bonded dimers in the solid state. Compounds 3 and 4 were tested in vitro for their antiproliferative activity against human colon carcinoma HT-29, estrogen receptor-responsive human breast adenocarcinoma MCF-7, estrogen-negative human breast adenocarcinoma MDA-MB-231, human promyelocytic leukemia HL-60 and human monocytic MonoMac6 cancer cells. Ferrocenyl-4-thiothymine-3,6-dihydro-2H-thiopyrane 3 showed a cytostatic effect on MonoMac6, MCF-7 and HL-60 cell lines, but was devoid of activity on MDA-MB-231 and HT-29 cells. In contrast, all cell lines tested were sensitive toward thymine derivative 4. Proapoptic activity of 3 and 4 was confirmed by means of acridine orange/ethidium bromide (AO/EB) double-staining assay. © 2015 Elsevier B.V.All rights reserved.


Egressy-Molnar O.,Corvinus University of Budapest | Magyar A.,MTA ELTE Research Group of Peptide Chemistry | Gyepes A.,Corvinus University of Budapest | Dernovics M.,Corvinus University of Budapest
RSC Advances | Year: 2014

2,3-Dihydroxy-propionyl (2,3-DHP) group is a specific residue detected in selenized yeast that forms numerous stable and highly abundant Se species in several different yeast strains and fermentation batches. The conjugated form of 2,3-DHP-selenocysteine and glutathione is one of the most abundant species that is found in nearly all selenized yeast. In order to overcome the commercial unavailability of this compound, its synthesis was carried out through the active ester formation of pentachlorophenyl glycerate with selenocysteine, followed by the redox conjugation with glutathione. The optimization process of the synthesis was utilized for the production of three other Se-yeast specific compounds, namely, the conjugate of glutathione and selenocysteine, the conjugate of 2,3-DHP-selenocysteine and selenocysteine, and di-N-2,3-dihydroxy- propionyl-selenocysteine. The upstream and clean-up procedures were supported and monitored with HPLC-UV, HPLC-ICP-MS, and HPLC-ESI-QQQMS set-ups, while the identification was performed with HPLC-ESI-QTOFMS. The synthesized 2,3-DHP-selenocysteine/selenocysteine conjugates possessed fragmentation patterns identical to literature data. © 2014 the Partner Organisations.


Kiss T.,Eötvös Loránd University | Gyulai G.,Eötvös Loránd University | Penzes C.B.,Eötvös Loránd University | Idei M.,Hungarian Academy of Sciences | And 3 more authors.
Colloids and Surfaces A: Physicochemical and Engineering Aspects | Year: 2014

Biodegradable poly(lactic-. co-glycolic acid)(PLGA 50:50) nanoparticles (NPs) were prepared and characterized in terms of size, composition, zeta potential and colloidal stability. Surface modification of PLGA NPs where primary amino groups were introduced to the Pluronic surface layer was developed. This method allows modulation of the charge character of the nanoparticle surface and provides functional groups for chemical reactions useful for targeting while retaining the aggregation stability of the system. The nanoparticles showed significant interaction with model membrane system (DPPC and DPPC. +. DPPG lipid layers) depending on the amount and type of Pluronic applied for stabilization of NPs.A new antitubercular drug candidate was encapsulated into the PLGA NPs. The cellular uptake and the intracellular efficacy against Mycobacterium tuberculosis ( Mtb) of the drug and the drug loaded nanoparticulate systems were investigated. These formulations were successfully taken up by MonoMac6 human monocyte cells and highly enhanced the availability and efficacy of the drug against Mtb which was demonstrated in comparative in vitro experiments. © 2014 Elsevier B.V.


Schreier V.N.,University of Konstanz | Petho L.,University of Konstanz | Petho L.,MTA ELTE Research Group of Peptide Chemistry | Orban E.,MTA ELTE Research Group of Peptide Chemistry | And 5 more authors.
PLoS ONE | Year: 2014

Targeted delivery of chemotherapeutic agents is a new approach for the treatment of cancer, which provides increased selectivity and decreased systemic toxicity. We have recently developed a promising drug delivery system, in which the anticancer drug daunorubicin (Dau) was attached via oxime bond to a gonadotropin-releasing hormone-III (GnRH-III) derivative used as a targeting moiety (Glp-His-Trp-Lys(Ac)-His-Asp-Trp-Lys(Dau = Aoa)-Pro-Gly-NH2; Glp = pyroglutamic acid, Ac = acetyl; Aoa = aminooxyacetyl). This bioconjugate exerted in vitro cytostatic/cytotoxic effect on human breast, prostate and colon cancer cells, as well as significant in vivo tumor growth inhibitory effect on colon carcinoma bearing mice. In our previous studies, H-Lys(Dau = Aoa)-OH was identified as the smallest metabolite produced in the presence of rat liver lysosomal homogenate, which was able to bind to DNA in vitro. To get a deeper insight into the mechanism of action of the bioconjugate, changes in the protein expression profile of HT-29 human colon cancer cells after treatment with the bioconjugate or free daunorubicin were investigated by mass spectrometry-based proteomics. Our results indicate that several metabolism-related proteins, molecular chaperons and proteins involved in signaling are differently expressed after targeted chemotherapeutic treatment, leading to the conclusion that the bioconjugate exerts its cytotoxic action by interfering with multiple intracellular processes. © 2014 Schreier et al.


Gaal A.,Eötvös Loránd University | Orgovan G.,Semmelweis University | Orgovan G.,Hungarian Academy of Sciences | Polgari Z.,Eötvös Loránd University | And 5 more authors.
Journal of Inorganic Biochemistry | Year: 2014

Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is a potential candidate in chelation therapy as an iron chelator. This study showed that a combined treatment with 2 μM easily available Fe(II), Cu(II) and Zn(II) each and 5 μM Dp44mT on eight different cancer cell lines resulted in a 10-40-fold increase in the intracellular Cu content compared to control samples. The uptake of Cu and Cu-dependent cytotoxicity strictly depend on the Cu concentration of the culture medium. Even as low concentration of Dp44mT as 0.1 μM can transport high amounts of copper inside the cells. The Cu accumulation and toxicity through Dp44mT can hardly be influenced by Fe. Copper uptake and toxicity triggered by 2 μM extracellular Cu(II) and 5 μM Dp44mT could not be influenced by Fe(II) extracellular concentrations even 50-times higher than that of Cu(II). A 50-times higher Co(II) extracellular concentration hindered the Cu(II) uptake almost completely and a 10-times higher Co(II) concentration already decreased the Dp44mT-mediated Cu toxicity. Conditional complex stability constant determinations for Dp44mT with Cu(II), Co(II), Fe(II), Ni(II) and Zn(II) revealed that the metal-to-ligand ratio is 1:1 in [Cu(II)Dp44mT] complex, while for Co(II), Fe(II) and Ni(II) is 1:2. The highest stability constant was obtained for Cu(II) (lg β = 7.08 ± 0.05) and Co(II) (lg β2 = 12.47 ± 0.07). According to our results, Dp44mT in combination with Cu is highly toxic in vitro. Therefore, the use of Dp44mT as an iron chelator is limited if biologically available Cu is also present even at low concentrations. © 2013 Elsevier Inc.


PubMed | MTA ELTE Research Group of Peptide Chemistry and Eötvös Loránd University
Type: | Journal: European journal of medicinal chemistry | Year: 2016

The emerging resistance of tumor cells against methotrexate (MTX) is one of the major limitations of the MTX treatment of tumorous diseases. The disturbance in the polyglutamation which is a main step in the mechanism of methotrexate action is often the reason of the resistance. Delivery of polyglutamylated MTX into cells may evade the mechanisms that are responsible for drug resistance. In this study conjugates of methotrexate and its pentaglutamylated derivatives with cell-penetrating peptides - penetratin and octaarginine - were investigated. The cellular-uptake and invitro cytostatic activity of conjugates were examined on breast cancer cell cultures (MDA-MB-231 as resistant and MCF-7 as sensitive cell culture). These cell cultures showed very different behaviour towards the conjugates. Although the presence of pentaglutamyl moiety significantly decreased the internalisation of conjugates, some of them were significantly active invitro. All of the conjugates were able to penetrate in some extent into both cell types, but only the conjugates of penetratin showed invitro cytostatic activity. The most effective conjugates were the MTX-Glu5-Penetratin(desMet) and MTX-Glu5-GFLG-Penetratin(desMet). The latter was effective on both cell cultures while the former was active only on the resistant tumor cells. Our results suggest that the translocation of polyglutamylated MTX may be a new way to treat sensitive and more importantly resistant tumors. While both penetratin and octaarginine peptides were successfully used to deliver several kinds of cargos earlier in our case the activity of penetratin conjugates was more pronounced.


PubMed | MTA ELTE Research Group of Peptide Chemistry and Eötvös Loránd University
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

Exploring copper(I)- and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HepG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first letter on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile.


PubMed | MTA ELTE Research Group of Peptide Chemistry and Eötvös Loránd University
Type: | Journal: Colloids and surfaces. B, Biointerfaces | Year: 2016

Novel peptide conjugates of two antitubercular drug candidates were synthesised and characterised using new tuftsin peptide derivative (OT14) as carrier moiety. As antitubercular drug candidates two pyridopyrimidine derivatives, TB803 (2-allylamino-4-oxopyrido[1,2-a]pyrimidine-3-carbaldehyde) and TB820 (4-oxo-2-(pyrrolidin-1-yl)-pyrido[1,2-a]pyrimidin-3-carbaldehyde) inhibiting vital enzyme of Mycobacterium tuberculosis were applied. Membrane affinity of the compounds TB803 and TB820 and their peptide conjugates was evaluated using experimental lipid mono- and bilayer models. Penetration ability was assessed tensiometrically from Langmuir monolayer study and applying quartz crystal microbalance for the supported lipid bilayer (SLB) system. Minimal inhibitory concentration (MIC) values remained in a similar micromolar range for both of the conjugates while their cellular uptake rate was improved significantly compared to the drug candidates. A correlation was found between membrane affinity properties and results of in vitro biological investigations. Analysis of physical/structural properties of SLB in contact with bioactive components and visualization of the structural change by atomic-force microscopy (AFM) provided information on the type and route of molecular interaction of drug construction with lipid layers. The possible role of electrostatic interactions between lipid layer and drug candidates was tested in Langmuir-balance experiments using negatively charged lipid mixture (DPPC+DPPG). Especially the peptide conjugates presented increased membrane affinity due to cationic character of the peptide sequence selected for the conjugate formation. That is supposed to be one reason for the enhanced cellular uptake observed in vitro on MonoMac6 cell line. The conjugation of antitubercular agents to a peptidic carrier is a promising approach to enhance membrane affinity, cellular uptake rate and in vitro selectivity.

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